PB1869: IGHV REPERTOIRE FEATURES IN KAZAKHSTAN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS
Authors: A. Klodzinskiy, L. Turgunova, M. Butyugina, M. Kakhanova, I. Pivovarova
Journal: HemaSphere (2022)

Background: The immunoglobulin heavy chain gene (IgHV) mutation is one of the most reliable predictive biomarkers in chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy. The incidence of CLL in Asia is about 10 times lower, than in Western countries and there are potential different IgHV genes mutations and stereotypy between Eastern and Western CLL. For instance, Chinese patients with CLL have higher percentage of mutated subgroup compared with European patients (55%) and different clinical presentation (Yi Xia et al., 2013; Marilisa Marinelli et al., 2016). The incidence of CLL in Kazakhstan is similar to that of the Western world, but to date nothing is known on the IgHV gene representation and mutations. Aims: The aim of the present study was to evaluate IgHV Repertoire Features In Kazakhstan Chronic Lymphocytic Leukemia Patients. Methods: The study included samples and medical records from 35 patients (19 male and 16 female) from the different regions of Kazakhstan. Participants’ ages ranged from 35 to 84 years (Median = 61). According to the European Research Initiative on CLL recommendations, IgHV mutational status was determined by amplifying the IgHV transcript by PCR, sequencing the gene through Sanger sequencing, and comparing the transcript to known germline genes available in immunoglobulin databases. We use the 2% cut-off to discriminate between mutated and unmutated rearrangements. Descriptive statistics for discrete variables included counts and frequency distributions. Results: Patients were divided into the four prognostic groups proposed by the CLL-IPI as follows: 6 (17.2%) at low risk, 16 (45.7%) at intermediate risk, 10 (28.6%) at high risk, and 3 (8.6%) at very high risk. The median observation time was 2.5 years. Eleven patients (31.4%) have no indications for treatment. 21 (60%) patients were treated with chemoimmunotherapy as first line and only 3 (12.5%) patients with 17p deletion received Ibrutinib. 20 (57.1%) had unmutated IGHV genes (U-CLL), 13 (37,1%) patients had mutated genes (M-CLL) and 2 (5.7%) cases carried double in-frame rearrangements. Prevalence of U-CLL which is consistent with their poor clinical outcome was close to Italian population (51%) and almost two times higher than among the Chinese patients (34%). The most of patients in this study were Caucasian (29; 83%) and only 6 patients (17%) were identified as Asians. In U-CLL group the most common IgHV genes were IGHV1-69 (8; 40%), IgHV1-2 (5; 25%), IgHV3-15 and IgHV4 (2; 10%). IgHV1-69 gene in the vast majority of cases was expressed in an unmutated state. In M-CLL most common IgHV genes were IGHV4, IgHV3 and IgHV2 without predominance of one of the subgroups and there were not any cases with IgHV1-69. Gender ratio in this study was 1:1 among patients with IgHV1-69 and all of them were Caucasian. During the study 4 participants with U-CLL died and two of them had IgHV 1-69 rearrangement. Summary/Conclusion: Hence, we conclude that Kazakhstan CLL patients show unique IgHV repertoire which is close to patients from western countries. Remarkably, IgHV1-69 was the most prevalent IgHV subgroup in Kazakhstan U-CLL patients (40%). IgHV1-69 gene is more associated with ethnicity, but not a gender.